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Factors Affecting Drug Metabolism Including Stereo Chemical Aspects


Metabolism is the biotransformation or chemical change of a medicine within the body to other molecular species known as metabolites by an enzymatic or non-enzymatic method. The liver is the principal site of drug metabolism; additional sites include the kidney, gut, lungs, and plasma.

A drug's metabolism may result in:
  • Inactivation: Most medications become inactive as a result of metabolism. For example, ibuprofen and paracetamol.
  • An active metabolite of a drug: For example, codeine and morphine, or primidone and phenobarbitone.
  • Inactive drug activation: For example, levodopa and dopamine, or prednisone and prednisolone.

Metabolic Enzymes

A medication must be digested by a variety of enzymes, which may be generally classified into two types:
  • Enzymes from Microsomal Enzymes - This enzyme is found in the liver, kidney, lungs, and intestinal mucosa on the smooth endoplasmic reticulum. Cytochrome p450, monooxygenase, glucuronyl transferase, and other enzymes are examples. Catalyzes oxidative, reductive, hydrolytic, and glucuronidation processes.
  • Non-microsomal Enzymes - This enzyme may be found in the cytoplasm and mitochondria of liver cells as well as in plasma. Flavoprotein oxidase, amidase, esterase, and conjugase are a few examples. All conjugations, several hydrolytic processes, and certain oxidation and reduction reactions are catalyzed by this enzyme.

Mechanism of Metabolism



Factors Affecting Drug Metabolism

The rate of drug metabolism is influenced by a variety of variables. These are some examples:

Genetic Factors

Biotransformation and xenobiotic conjugation exhibit species variations. Genetic variations between people or ethnic groups might result in an excessive or extended therapeutic effect or hazardous overdose.

Physiological Factors

Because the very young and extremely elderly have reduced metabolism, age is an issue. Harmonics (including those caused by stress), sex differences, pregnancy, changes in intestinal microbiota, illnesses (particularly those involving the liver), and dietary condition can all have an impact on xenobiotic metabolism.

Pharmacodynamic Factors

The dose, frequency, and route of administration, in addition to its tissue distribution, determine its metabolic rate.

Environmental Factors

Metabolism is affected by competition for metabolizing enzymes with various xenobiotics and medicines, as well as poisoning of enzymes by toxic chemicals such as carbon monoxide or pesticide synergists.

Biological Factors

Age

  • The drug metabolic rate varies between age groups mostly owing to differences in enzyme content, enzyme activity, and haemodynamics.
  • The microsomal enzyme system is not fully formed in neonates (up to 2 months) and newborns (2 months to 1 year). As a result, many medications are digested slowly. Caffeine, for example, has a half-life of four days in neonates vs four hours in adults.
  • Children (aged 1 to 12 years) metabolize numerous medicines significantly faster than adults, with the rate of metabolism peaking between the ages of 6 and 12 years. As a result, kids require a higher mg/kg dosage than adults.
  • As a result of decreased cardiac output, liver size, microsomal enzyme activity, and hepatic blood flow all decrease in the elderly, all of which contribute to decreased drug metabolism. Chlomethiazole, for example, has a high absorption in the elderly, requiring a lower dosage.


Diet

A variety of dietary components influence enzyme content and function. In general,
  • A low protein diet reduces drug metabolizing capacity, whereas a high protein diet enhances drug metabolizing ability because protein diet promotes enzyme production and raises the quantity of amino acids for drug conjugation.
  • Because phospholipids, which are key components of microsomes, are depleted, a fat-free diet lowers cytochrome P-450 levels.
  • Many medications' metabolism is inhibited by grapefruit, which improves their oral bioavailability.
  • Diets deficient in vitamins (such as vitamins A, B2, B3, C, and E) and minerals (such as iron, calcium, magnesium, and zinc) slow enzyme metabolism.
  • Starvation causes a reduction in the amount of glucuronides produced compared to normal circumstances.

Sex Difference

Since differences between male and female are apparent after puberty. As a result, sex-related changes in metabolic rate may be caused by sex hormones. Such sex differences have been extensively researched in rats, where male rats have a larger drug metabolizing ability. Women metabolize benzodiazepines more slowly than males. Several studies have found that women using contraceptive tablets metabolize a variety of medications slowly.

Species Difference

In both Phase I and Phase II reactions, species differences were identified. Both qualitative and quantitative changes in the enzyme and its activity have been detected in Phase-I reactions. The presence or lack of particular enzymes in different species causes qualitative variations. Variations in the number and localization of enzymes, the number of natural inhibitors, and enzyme competition for certain substrates all contribute to quantitative disparities. Human livers have fewer cytochrome P-450 per gramme of tissue than other species' livers. Cytochrome P450 concentrations in rat liver range from 30 to 50 nmol/g, whereas human liver concentrations range from 10 to 20 nmol/g. Furthermore, human liver accounts for 2% of body weight, but rat liver accounts for around 4%. Similarly, in men, amphetamine and ephedrine are largely metabolized by oxidative deamination, but in rats, aromatic oxidation is the predominant mechanism. Similarly, in pigs, the phenol is excreted mostly as glucuronide, but in cats, the sulphate conjugate predominates.

Stereochemical Factors

Stereochemical factors, in general, have a substantial influence on how the drug molecule interacts with target receptors to generate its pharmacological reaction. Similarly, preferential interaction of one stereoisomer with drug metabolizing enzymes may result in differences in metabolism between the two enantiomers of a racemic combination. In humans, several medications (for example, warfarin, propranolol, hexobarbital, glutethimide, cyclophosphamide, ketamine, and ibuprofen) are frequently provided as racemic combinations. The pharmacological activity of the two enantiomers in a racemic mixture may be different. (+)-alpha-propoxyphene (Darvon) is an analgesic, whereas (-)-alpha-propoxyphene (Novrad) is antitussive. One enantiomer is usually significantly more active than the other.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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